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Abstract Traumatic brain injury (TBI) impacts millions of people globally, however currently there are no approved therapeutics that address long‐term brain health. In order to create a technology that is relevant for siRNA delivery in TBI after systemic administration, sub‐100 nm nanoparticles with rolling circle transcription (RCT) are synthesized and isolated in order improve payload delivery into the injured brain. Unlike conventional RCT‐based RNA particles, in this method, sub‐100 nm RNA nanoparticles (RNPs) are isolated. To enhance RNP pharmacokinetics, RNPs are synthesized with modified bases in order to graft polyethylene glycol (PEG) to the RNPs. PEGylated RNPs (PEG‐RNPs) do not significantly impact their knockdown activity in vitro and lead to longer blood half‐life after systemic administration and greater accumulation into the injured brain in a mouse model of TBI. In order to demonstrate RNA interference (RNAi) activity of RNPs, knockdown of the inflammatory cytokine TNF‐α in injured brain tissue after systemic administration of RNPs in a mouse model of TBI is demonstrated. In summary, small sub‐100 nm multimeric RNA nanoparticles are synthesized and isolated that can be modified using accessible chemistry in order to create a technology suitable for systemic RNAi therapy for TBI. 

Abstract Current screening and diagnostic tools for traumatic brain injury (TBI) have limitations in sensitivity and prognostication. Aberrant protease activity is a central process that drives disease progression in TBI and is associated with worsened prognosis, thus direct measurements of protease activity can provide more diagnostic information. In this study, a nanosensor is engineered to release a measurable signal into the blood and urine in response to activity from the TBI‐associated protease calpain. Readouts from the nanosensor are designed to be compatible with ELISA and lateral flow assays, clinically‐relevant assay modalities. In a mouse model of TBI, the nanosensor sensitivity is enhanced when ligands that target hyaluronic acid are added. In evaluation of mice with mild or severe injuries, the nanosensor identifies mild TBI with a higher sensitivity than the biomarker glial fibrillary acidic protein (GFAP). This nanosensor technology allows for measurement of TBI‐associated proteases without the need to directly access brain tissue and has the potential to complement existing TBI diagnostic tools.